Synthesis, Structure and Impact of 5-Aminoorotic Acid and Its Complexes with Lanthanum(III) and Gallium(III) on the Activity of Xanthine Oxidase.

The superoxide radical ion is involved in numerous physiological processes, associated with both health and pathology. Its participation in cancer onset and progression is well documented. Lanthanum(III) and gallium(III) are cations that are known to possess anticancer properties. Their coordination complexes are being investigated by the scientific community in the search for novel oncological disease remedies. Their complexes with 5-aminoorotic acid suppress superoxide, derived enzymatically from xanthine/xanthine oxidase (X/XO). It seems that they, to differing extents, impact the enzyme, or the substrate, or both. The present study closely examines their chemical structure by way of modern methods-IR, Raman, and 1H NMR spectroscopy. Their superoxide-scavenging behavior in the presence of a non-enzymatic source (potassium superoxide) is compared to that in the presence of an enzymatic source (X/XO). Enzymatic activity of XO, defined in terms of the production of uric acid, seems to be impacted by both complexes and the pure ligand in a concentration-dependent manner. In order to better relate the compounds' chemical characteristics to XO inhibition, they were docked in silico to XO. A molecular docking assay provided further proof that 5-aminoorotic acid and its complexes with lanthanum(III) and gallium(III) very probably suppress superoxide production via XO inhibition.

In Vitro Interaction of 5-Aminoorotic Acid and Its Gallium(III) Complex with Superoxide Radical, Generated by Two Model Systems.

Increased levels of the superoxide radical are associated with oxidative damage to healthy tissues and with elimination of malignant cells in a living body. It is desirable that a chemotherapeutic combines pro-oxidant behavior around and inside tumors with antioxidant action near healthy cells. A complex consisting of a pro-oxidant cation and antioxidant ligands could be a potential anticancer agent. Ga(III) salts are known anticancer substances, and 5-aminoorotic acid (HAOA) is a ligand with antioxidant properties. The in vitro effects of HAOA and its complex with Ga(III) (gallium(III) 5-aminoorotate (GaAOA)) on the in vitro accumulation of superoxide and other free radicals were estimated. Model systems such as potassium superoxide (KO2), xanthine/xanthine oxidase (X/XO), and rat blood serum were utilized. Data suggested better antioxidant effect of GaAOA compared to HAOA. Evidently, all three ligands of GaAOA participated in the scavenging of superoxide. The effects in rat blood serum were more nuanced, considering the chemical and biochemical complexity of this model system. It was observed that the free-radical-scavenging action of both compounds investigated may be manifested via both hydrogen donation and electron transfer pathways. It was proposed that the radical-scavenging activities (RSAs) of HAOA and its complex with Ga(III) may be due to a complex process, depending on the concentration, and on the environment, nature, and size of the free radical. The electron transfer pathway was considered as more probable in comparison to hydrogen donation in the scavenging of superoxide by 5-aminoorotic acid and its gallium(III) complex.

Lanthanum, Gallium and their Impact on Oxidative Stress.

The role metals play in living organisms is well established and subject to extensive research. Some of them participate in electron-exchange reactions. Such reactions cause generation of free radicals that can adversely impact biological systems, as a result of oxidative stress. The impact of 'non-biological' metals on oxidative stress is also a worthy pursuit due to the crucial role they play in modern civilization. Lanthanides (Ln) are widely used in modern technology. As a result, human exposure to them is increasing. They have a number of established medical applications and are being extensively researched for their potential antiviral, anticancer and anti-inflammatory properties. The present review focuses on lanthanum (La) and its impact on oxidative stress. Another metal, widely used in modern high-tech is gallium (Ga). In some respects, it shows certain similarities to La, therefore it is a subject of the present review as well. Both metals exhibit ionic mimicry which allows them to specifically target malignant cells, initiating apoptosis that makes their simple salts and coordination complexes promising candidates for future anticancer agents.

Cerium(III) and neodymium(III) complexes as scavengers of X/XO-derived superoxide radical.

The cerium (III) and neodymium (III) complexes with 3,3'-benzylidenebis[4-hydroxycoumarin] were synthesized and characterized by different analytical and spectral methods. The synthesis of these complexes is taken into consideration with cytotoxic screening and study of their antioxidant effect. Their cytotoxicity toward cancerous cell cultures correlated with the weakness of the coordinative bond between the cation and organic ligand and with the capability to scavenge superoxide radicals as well. On the basis of the data reported by us earlier and our new results, it was proposed that cerium (III) complex with 3,3'-benzylidenebis[4-hydroxycoumarin] might induce intracellular acidification along with control over the extracellular oxidative stress.